Ifosfamide is a cytotoxic alkylating agent. It has a similar spectrum of activity to cyclophosphamide. It has been shown to be more effective and less toxic than cyclophosphamide when given by pulsed or infusional regimes. The compound is licensed for use in refractory testicular cancer in the U.S., and for tumors of lung, ovary, cervix, breast and testis and soft tissue sarcoma in the UK. It is used as a single agent and in combination with radiotherapy, surgery and other cytotoxic agents.
Ifosfamide is a cytotoxic compound and effects other than the antitumor effect are expected. Myelosuppression, alopecia, nausea and vomiting are all unwanted effects of the compound.
The compound has other unwanted toxicities, e.g. on the urinary tract, and neurotoxicity, which limit the dosing and make the compound difficult to use. Combination with the uroprotective agent mesna has reduced the incidence of haemorrhagic cystitis, but nephrotoxicity is a potentially serious side-effect.
Neurotoxic effects range from mild somnolence to severe encephalopathy, hallucinations and coma. In most cases, they are reversible, but in some they are not. They are more prevalent after oral dosing and large single IV doses. It is thought that they are caused by a metabolite, possibly chloroacetaldehyde. This is a significant problem: the drug must be administered in hospital because of the occurrence of these side-effects.
CNS side-effects were a major dose-limiting side-effect when the compound was in development as an oral formulation. The side-effects appeared at a much lower dose than they did during iv administration, and this meant that cytotoxic doses could not be reached. It is known that there is much more metabolism of the compound after oral dosing; in particular, higher levels of chloroacetaldehyde are produced, indicating more N-dechloroethylation.
Ifosfamide is a chiral compound. Its enantiomers dexifosfamide (herein sometimes "(R)-IFF") and levoifosfamide (herein sometimes "(S)-IFF") are known, and may be prepared by classical resolution. Processes for their preparation are described in U.S. Pat. No. 4,684,742, Polish Patent No. 119,971, and British Patent No. 1,553,984.
Ifosfamide requires metabolic activation. One of the two main metabolic pathways produces the active species, the isophosphoramide mustard. The 4-hydroxy-ifosfamide may also be an active species. The second main pathway, N-dechloroethylation, produces 2 and 3-dechloro metabolites, with the release of chloroacetaldehyde. S-Ifosfamide produces R-3-dechloroifosfamide (R-3DCE) and S-2-dechloroifosfamide (S-2DCE). R-ifosfamide produces S-3-dechloroifosfamide (S-3DCE) and R-2-dechloroifosfamide (R-2DCE). Other metabolic routes are responsible for a very small amount of the total metabolism. Metabolism is induced by dividing the dose over several days; the main increase being in the route to the mustard. On a single dose, between 20-40% of the drug is excreted unchanged, and 15-50% of the compound is metabolised through the N-dechloroethylation pathway.
Boos et al, Cancer Chemother. Pharmacol. 28:455-460 (1991), investigated the urinary excretion of the enantiomers of ifosfamide, following administration of the racemate. It was concluded that "Theoretically, an advantage in the form of reduced side-chain metabolism could be expected from the use of the S form of ifo in nearly half of our patients and the R form in the other half", and "stereospecific metabolism does not indicate that any clear-cut advantage can be gained from the application of an individual enantiomer."
Masurel et al, Cancer Res. 50: 252-255 (1990), studied the efficacy and toxicity of IFF enantiomers in CBA/CaJ mice. The results indicated that there were no statistically significant differences between the efficacies of (R)-IFF, (S)-IFF, and (R,S)-IFF against childhood rhabdomyosarcoma (HxRh28) grown in vivo as a xenograft in immunoincompetent female CBA/CaJ mice. The same was true regarding the acute toxicities of the stereoisomers. No statistically significant differences were found in the plasma pharmacokinetics of (S)-IFF, or in the in vitro N-dechloroethylation.